Natural History of Mouse Syngeneic Lymphoma: Morphologic and Immunologic Aspects

The morphologic changes in lymphoreticular tissues and development of antitumor immune reactions of specific pathogen-free mice injected with syngeneic lymphoma cells were sequentially analyzed. The regional (right inguinal) lymph node demonstrated mild changes indicative of immunologic response. Systemic lymph nodes revealed a moderate degree of immune response on morphologic basis. The spleen was the site of marked activity, characterized by the presence of large pyroninophilic cells and germinal centers. Foci of necrosis in the local tumor accompanied by mature lymphocytes suggested cell-mediated immune rejection. Mice developed circulating antibodies 2 days after implantation. No antibodies were demonstrated attached to fresh tumor cells. Lymphocyte cytotoxic activity was demonstrated beginning on day 4. Both cytotoxic activity and circulating antibodies were no longer detectable after the third week following tumor implantation. Tumor-bearing mice also had an impaired capacity to mount a primary immune reaction to sheep red blood cells. The spleen demonstrated a marked loss of lymphocytes and the subsequent appearance of masses of amyloid material. It is suggested that amyloidosis in lymphoreticular organs is the result of a derangement in the immune response of the host following a prolonged and sustained antigenic stimulation. It appears that in syngeneic pathogen-free mice the spleen plays the major role in immune rejection mechanisms while the draining node only plays a modest role.     

Albendazolesulphoxide concentrations in plasma and hydatid cyst and prediction of parasitological and clinical outcomes in patients with liver hydatidosis caused by Echinococcus granulosus

Aim

To investigate the relationship between plasma and cyst concentrations of albendazolesulphoxide (ASO) and their effects on parasitological findings and disease recurrence in patients with liver hydatidosis.

Methods

The study was conducted at the University Hospital for Infectious Diseases “Dr. Fran Mihaljević,” Zagreb, Croatia, between August 2006 and January 2011. Consecutive patients (N = 48, age 6-77 years) were treated with albendazole (3 × 5 mg/kg/d) over 28 days before surgical cyst removal (n = 34) or percutaneous evacuation (PAIR) (n = 14). Plasma ASO was determined on days 10 and 28 of treatment and cyst concentrations at surgery/PAIR.

Results

Disease recurred in 3 surgically treated patients. Variability of ASO concentrations was substantial. Plasma concentrations on day 10 were higher than on day 28 (geometric means ratio [GMR] 2.00; 95%CI 1.38-2.91, P < 0.001) and higher than cyst concentrations at the time of treatment (GMR = 1.58, 1.01-2.34, P = 0.045). Higher cyst (but not plasma) concentrations were independently associated with lower odds of protoscolex motility (OR = 0.23, 0.01-0.70, P < 0.001) and higher odds of protoscolex destruction (OR = 1.17, 1.04-1.46, P < 0.001). With adjustment for age and protoscolex motility, higher day 10 plasma concentrations (but not cyst concentrations) were associated with lower odds of disease recurrence (OR = 0.49, 0.09-0.97, P = 0.035). Plasma concentrations did not predict cyst concentrations.

Conclusion

Viability of protoscolices progressively decreased with increasing ASO concentrations in the cyst. Data strongly suggested that higher plasma concentrations reduced the risk of disease recurrence.Echinococcosis or hydatid cyst disease is an anthropozoonosis caused by the larvae of E. granulosus, E. multilocularis, E. vogeli, and E. oligarthus (1). In transient hosts (eg, sheep, cattle, pigs, humans), the parasite develops in the form of hydatid cyst(s) of different sizes. The cyst consists of the outer layer (ectocyst), made of dense fibrous tissue; the middle layer (endocyst), which is elastic and lamellar in structure; and the inner (germinative) layer, which gives rise to buds that develop into scolices. The cyst content is hydatid fluid, produced by the germinative layer. In humans, the most commonly invaded organs are the liver and the lungs, but practically all organs can be affected (1-3). In Croatia, the disease is caused exclusively by E. granulosus. According to the European Hospital Morbidity Database (4) for the period 2010-2012, age-adjusted annual hospital admission rates due to echinococcosis (ICD-B67) in Croatia varied between 0.011 and 0.0167/1000 population (ie, between 51 and 86 cases/y), indicating that the diseases is relatively rare but still stably present.Treatments for hydatid cyst disease include surgical removal of the cyst(s) (still most commonly used method); percutaneous aspiration of the cyst with instillation of a scolicidal agent (95% ethanol or hypertonic saline [15%-20%] or albendazole), ie, the PAIR (puncture, aspiration, instillation, and re-aspiration) procedure, which seems to have greater clinical efficacy and lower rate of complications than the surgical procedure; and treatment with benzimidazole anthelmintic drugs. The latter, pharmacological option might be used as a monotreatment in the case of smaller cysts or when invasive approaches are not feasible, but it is typically adjunctive treatment to surgery or PAIR used to prevent dissemination of scolices from ruptured cysts. In this setting, benzoimidazoles are used over at least 4 weeks before the definitive treatment (5-8). Among benzoimidazoles, albendazole is considered a cornerstone pharmacological treatment of echinococcosis. Although some controversies still exist regarding optimal dosing, the most widely accepted regimen implies administration of 10-15 mg/kg/d (5-8). Upon oral ingestion (with a fatty meal to increase bioavailability), albendazole is rapidly metabolized (first-pass metabolism in the liver) into the active form albendazolesulphoxide (ASO), which inhibits tubuline polymerization in the parasite microtubules and inactivates cell division (9). Greater systemic bioavailability is considered an important advantage of albendazole over mebendazole, the other member of the group (9). Although ASO has been shown to penetrate both the hepatic and non-hepatic cysts (9,10), the prognostic value of plasma and/or cyst concentrations has not been elucidated. Therefore, we aimed to relate ASO concentrations in the plasma and in the cysts, and to investigate their relationship with the parasitological and clinical outcomes in patients with liver hydatidosis treated with albendazole over one month prior to surgical treatment or PAIR.     

Fertility-sparing surgery for patients with malignant ovarian germ cell tumors: 10 years of clinical experience from a tertiary referral center

Archives of Gynecology and Obstetrics - To describe a case series of patients with malignant ovarian germ cell tumors (MOGCT) treated exclusively with fertility-sparing surgery (FSS) with or...     

Polymorphisms in B3GAT1, SLC9A9 and MGAT5 are associated with variation within the human plasma N-glycome of 3533 European adults

The majority of human proteins are post-translationally modified by covalent addition of one or more complex oligosaccharides (glycans). Alterations in glycosylation processing are associated with numerous diseases and glycans are attracting increasing attention both as disease biomarkers and as targets for novel therapeutic approaches. Using a recently developed high-throughput high-performance liquid chromatography (HPLC) analysis method, we have reported, in a pilot genome-wide association study of 13 glycan features in 2705 individuals from three European populations, that polymorphisms at three loci (FUT8, FUT6/FUT3 and HNF1A) affect plasma levels of N-glycans. Here, we extended the analysis to 33 directly measured and 13 derived glycosylation traits in 3533 individuals and identified three novel gene association (MGAT5, B3GAT1 and SLC9A9) as well as replicated the previous findings using an additional European cohort. MGAT5 (meta-analysis association P-value = 1.80 × 10(-10) for rs1257220) encodes a glycosyltransferase which is known to synthesize the associated glycans. In contrast, neither B3GAT1 (rs7928758, P = 1.66 × 10(-08)) nor SLC9A9 (rs4839604, P = 3.50 × 10(-13)) had previously been associated functionally with glycosylation of plasma proteins. Given the glucuronyl transferase activity of B3GAT1, we were able to show that glucuronic acid is present on antennae of plasma glycoproteins underlying the corresponding HPLC peak. SLC9A9 encodes a proton pump which affects pH in the endosomal compartment and it was recently reported that changes in Golgi pH can impair protein sialylation, giving a possible mechanism for the observed association.     

Influence of haemodialysis on early markers of atherosclerosis

Introduction: End-stage renal disease (ESRD) patients treated by haemodialysis (HD) have impaired endothelium-dependent vasodilatation and increased intima-media thickness (IMT) of the carotid artery The aim of the study was to analyse the relationships between parameters of chronic HD treatment and non-invasive assessments of preclinical atherosclerosis (endothelial dysfunction and carotid IMT) in ESRD patients on HD. Methods: Fifty-two (19 females, 33 males) adult patients on chronic maintenance (4.65 ± 3.29 years) HD aged 59.88 ± 15.49 years were investigated. Ultrasonographic studies were performed with a 7.5 MHz high-resolution probe. The common carotid artery IMT was measured. Brachial artery diameter was analysed to the rest. In order to assess flow-mediated dilatation (FMD), hyperaemia was induced by a pneumatic cuff, and an analysis of the diameter was performed 1, 2, 3 and 4 min after cuff deflation. Results: Significant differences were found in the average carotid IMT value between subjects with delivered dialysis dose (Kt/V) ≥1.2 and <1.2 (0.89 ± 0.21 vs 1.04 ± 0.11, P = 0.0045). A correlation between Kt/V and IMT (r = 0.366, P = 0.004) was demonstrated. FMD values of the brachial artery did not correlate with Kt/V. A correlation between low molecular weight heparin per kg of body mass and maximal percent of FMD was demonstrated (r = −0.242, P = 0.049). The maximal percent of brachial FMD was correlated with absolute difference between pre- and postdialysis pulse pressure values (r = −0.265, P = 0.033). In a partial correlation with haemoglobin as control, a variable significant correlation between total erythropoietin dose and maximal carotid IMT (r = −0.262, P = 0.036) was found. In a multiple linear regression model, Kt/V was independently correlated with carotid IMT values (β = −0.227, P = 0.0335). Conclusion: This study has demonstrated the association between HD procedure and early atherosclerosis markers. HD treatment has to be considered as potential modifying factor in atherosclerosis development.     

Effects of Halothane on Excitatory Neurotransmission to Medullary Expiratory Neurons in a Decerebrate Dog Model

Background: The activity of canine expiratory (E) neurons in the caudal ventral respiratory group is primarily dependent on N-methyl-d-aspartic acid (NMDA) receptor-mediated excitatory chemodrive inputs and modulated by an inhibitory mechanism mediated via [gamma]-aminobutyric acidA (GABAA) receptors. In an intact canine preparation, halothane depressed the activity of these neurons mainly by reduction in overall glutamatergic excitation. A new decerebrate preparation allows comparison of the effects of halothane on these synaptic mechanisms with an anesthetic-free baseline state.

Methods: Two separate studies were performed in decerebrate, vagotomized, paralyzed, mechanically ventilated dogs during hypercapnic hyperoxia. In study 1, the effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded E neuronal activity was studied before and during complete GABAA receptor blockade by localized pressure ejection of bicuculline. Complete blockade of the inhibitory mechanism allowed differentiation between the effects of halothane on overall GABAA-mediated inhibition and on overall NMDA receptor-mediated excitation. In study 2, the effect of 1 MAC halothane on the dose response of neurons to localized picoejection of the glutamate agonist NMDA was used to estimate halothane effect on postsynaptic glutamatergic excitatory neurotransmission.

Results: In study 1, the spontaneous activity of 14 E neurons was depressed 38.6 +/- 20.6% (mean +/- SD) by 1 MAC halothane. Overall excitation was depressed 31.5 +/- 15.5%. The GABAergic inhibition showed a 11.7 +/- 18.3% enhancement during halothane. In study 2, the spontaneous activity of 13 E neurons was again significantly depressed by 1 MAC halothane (27.9 +/- 10.6%), but the postsynaptic response of the neurons to exogenous NMDA was not significantly depressed by halothane (3.3 +/- 38.4%).     

Long-Term Results of Surgery for Temporal Bone Paraganglioma

The only way to resolve the dispute about the effectiveness of surgery versus radiation therapy for glomus tympanicum and jugulare tumors is adequate long-term studies. In a retrospective study with an average follow-up period of 15 years (range 11 to 23 years) we reassessed 11 patients with glomus tympanicum tumors and 11 patients with glomus jugulare tumors. Ten of 11 patients with glomus tympanicum tumor were tumor-free after surgery. A temporary facial palsy and an external meatal wall defect were the only surgical complications. The air-bone gap postoperatively closed to within 10 dB in three patients, to within 20 dB in six patients, and to more than 30 dB in one patient. Nine of 10 patients with glomus jugulare tumor receiving complete resection were tumor-free. Less than half the patients experienced new-onset cranial nerve function loss, and all made satisfactory recovery, eliminating the need for tracheostomy or gastrostomy. In two patients, the hearing could be preserved on the preoperative level, but the majority already presented with deafness. In the long-term, surgery remains a treatment of choice for glomus tympanicum tumors. It is also an extremely effective treatment with low morbidity for glomus jugulare tumors, including those with intracranial extension.     

C-reactive protein,renal function,and cardiovascular outcome in patients with symptomatic peripheral artery disease and preserved left ventricular systolic function

AimTo investigate the prognostic role of C-reactive protein (CRP) and renal function for the occurrence of major adverse cardiovascular events (MACE) in patients with symptomatic peripheral artery disease (PAD) and preserved left ventricular ejection fraction (LVEF).MethodsThe occurrence of MACE, defined as composite endpoint of acute myocardial infarction, urgent coronary revascularization, stroke, and death was assessed in 319 consecutive PAD patients admitted to the University Hospital between January 2010 and January 2014 (66.5% men, mean [±standard deviation] age 70 ± 10 years, mean ankle brachial index 0.58 ± 0.14) with normal LVEF (>50%). Multivariate Cox regression analysis adjusted for age, sex, traditional cardiovascular risk factors, anemia, polyvascular disease, critical limb ischemia (CLI), statin treatment, CRP (>5 mg/L), and impaired renal function (estimated glomerular filtration rate <60 mL/min) was applied to assess the independent predictors of MACE.ResultsDuring median follow-up period of 24 months (interquartile range, 16-34 months), 77 patients (24%) experienced MACE. Compared to patients without MACE, these patients were older, more likely to have CLI, polyvascular disease, anemia, elevated CRP, and impaired renal function. In multivariate regression analysis, age (HR 1.04, 95% CI 1.01-1.07), polyvascular disease (HR 1.95, 95% CI 1.23-3.09), elevated CRP (HR 1.89, 95% CI 1.18-3.02), and impaired renal function (HR 1.68, 95% C 1.01-2.78) remained independent predictors of MACE. Patients with both impaired renal function and high CRP values on admission were 3.59 times more likely to experience MACE than patients with normal CRP and preserved renal function.ConclusionElevated admission CRP and renal impairment are independent predictors of MACE in symptomatic PAD patients with preserved LVEF.C-reactive protein (CRP) is a simple marker, widely commercially available and regularly used in daily clinical practice. While CRP is well studied in acute coronary syndromes, its predictive role in symptomatic peripheral artery disease (PAD) is less clear (1). Conflicting data were published regarding the prognostic significance of admission CRP in patients with PAD (2-5). Its prognostic relevance may be affected by disease severity, duration of follow-up period, and inclusion of traditional risk factors.Patients with chronic kidney disease have an increased risk of developing PAD (6,7). Data regarding the prognostic implication of impaired renal function in PAD patients are scarce. Despite interrelated pathophysiology of inflammation and renal function, their prognostic role has not been clarified in the clinical setting of symptomatic PAD. Left ventricular systolic dysfunction is associated with worse outcome and its prevalence is significantly higher in patients with peripheral vascular disease than in general population (8,9). However, this parameter was not included in prior outcome studies. Therefore, the aim of our research was to investigate the prognostic impact of CRP and impaired renal function for MACE in a cohort of consecutive patients with symptomatic PAD and preserved left ventricular systolic function.     

Metallization-Induced Quantum Limits of Contact Resistance in Graphene Nanoribbons with One-Dimensional Contacts

Graphene has attracted a lot of interest as a potential replacement for silicon in future integrated circuits due to its remarkable electronic and transport properties. In order to meet technology requirements for an acceptable bandgap, graphene needs to be patterned into graphene nanoribbons (GNRs), while one-dimensional (1D) edge metal contacts (MCs) are needed to allow for the encapsulation and preservation of the transport properties. While the properties of GNRs with ideal contacts have been studied extensively, little is known about the electronic and transport properties of GNRs with 1D edge MCs, including contact resistance (R_C), which is one of the key device parameters. In this work, we employ atomistic quantum transport simulations of GNRs with MCs modeled with the wide-band limit (WBL) approach to explore their metallization effects and contact resistance. By studying density of states (DOS), transmission and conductance, we find that metallization decreases transmission and conductance, and either enlarges or diminishes the transport gap depending on GNR dimensions. We calculate the intrinsic quantum limit of width-normalized R_C and find that the limit depends on GNR dimensions, decreasing with width downscaling to ~21 Ω∙µm in 0.4 nm-wide GNRs, and increasing with length downscaling up to ~196 Ω∙µm in 5 nm-long GNRs. We demonstrate that 1D edge contacts and size engineering can be used to tune the R_C in GNRs to values lower than those of graphene.     

Overview of vasculitis and vasculopathy in rheumatoid arthritis—something to think about

The vasculature plays a crucial role in inflammation and atherosclerosis associated with the pathogenesis of rheumatoid arthritis. Vasculitis in rheumatoid arthritis is associated with longstanding disease, has an important impact on a patient’s quality of life and influences patient life expectancy. Seropositivity, specific human leukocyte antigen variations, antibodies to cyclic citrullinated peptides, and cigarette smoking are among the genetic and environmental predictors of rheumatoid vasculitis. Atherosclerosis is an early and common finding in rheumatoid arthritis and it correlates with disease duration, activity, and severity. Apart from conventional risk factors such as cigarette smoking, physical inactivity, obesity, arterial hypertension, dyslipidemia and diabetes mellitus, rheumatoid arthritis-related risk factors including disease duration, severity and activity, rheumatoid factor and antibodies to cyclic citrullinated peptides status, functional impairment, C-reactive protein, radiographic changes, presence of the shared epitope, and treatment modalities are all implicated in the development of accelerated atherosclerosis. Atherosclerosis is also considered an inflammatory disease; thus, it may share common pathogenic mechanisms with rheumatic diseases such as rheumatoid arthritis. Advances in treatment of rheumatoid arthritis with disease-modifying biologic and nonbiologic agents will probably continue to reduce the incidence of vasculitis. Since the goal of treatment for rheumatoid arthritis is to decrease inflammatory burden, successful treatment may theoretically reduce the risk of accelerated atherosclerosis.